In the setting of hypertrophic cardiomyopathy (HCM), ischemia plays a possibly under-evaluated role. In particular, a large body of evidence indicates that structural and functional abnormalities in the coronary microcirculation contribute to myocardial ischemia and are key elements for HCM pathophysiology and clinical evolution. Measurement of myocardial blood flow (MBF) at rest and under maximal hyperemia (hMBF) by means of perfusion positron-emission tomography (PET) is the most effective way to assess microvascular dysfunction in humans. Therefore, hMBF abnormalities reflect HCM severity and correlate with other important features, such as ischemic symptoms and myocardial fibrosis. Most importantly, it has been demonstrated that severely blunted hMBF implies an adverse outcome in HCM patients. Therefore, PET could be helpful for stratifying patient prognosis and should be used in selected patient subsets to identify those at risk of unfavorable evolution.